Yukio Naya md, Section for Medical Robotics and Surgical Device Creation, Research Center for Frontier Medical Engineering, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan. Email: firstname.lastname@example.org
Objective: We evaluated the efficacy of low dose tamsulosin after extracorporeal shock wave lithotripsy (ESWL) in Japanese male patients with ureteral stone.
Methods: One hundred and two Japanese male patients with ureteral stones who underwent ESWL were randomly divided into three groups. Group A (38 patients) was given tamsulosin (0.2 mg/day); group B (30 patients) was given c horeito, a herbal medicine (7.5 g/day); and group C (34 patients) received no medication. Stone clearance was assessed at 1, 7, 14, and 28 days after ESWL using plain abdominal radiography and abdominal ultrasonography. After 28 days, stone delivery was checked every 2 weeks.
Results: The stone-free rate was 84.21%, 90%, and 88.24% for groups A, B, and C, respectively (P = 0.3425). The mean expulsion time was 15.66 ± 6.14 days in group A, 27.74 ± 25.36 days in group B, and 35.47 ± 53.70 days in group C. The expulsion time of group A was significantly shorter than that of groups B (P = 0.0116) and C (P = 0.0424).
Conclusions: The addition of tamsulosin to conservative treatment appeared to be effective in shortening the stone expulsion time.
The lifetime risk of urolithiasis is estimated to be between 8% and 15% in Western countries.1 Urolithiasis is a common disease that urologists must routinely treat. Currently, extracorporeal shock wave lithotripsy (ESWL), a minimally invasive technology, is a primary treatment for urolithiasis. The success of this procedure is determined by three factors: fragmentation, nature of the calculus, and clearance. Fragmentation is dependent on lithotripter type. The nature of the calculus depends on its size and configuration, as well as the number and location of the stones. Clearance depends on ureteral muscle spasm, submucosal edema, and ureteral infection, which are all modifiable factors. Recently, several studies, both in watchful waiting patients and post-ESWL patients, have suggested that the alpha-1 adrenergic blocker tamsulosin inhibits these modifiable factors and facilitates stone passage.2,3 However, these studies used a dose of tamsulosin (0.4 mg/daily) that is not accepted in Japan, where the accepted dose is less than 0.2 mg. Furthermore, there have been no studies in Japan using alpha-1 adrenergic blockers to facilitate stone delivery.
Kampo medicine (Eastern herbal therapy) is a traditional Japanese therapeutic system that originated in China and has been used to treat various diseases for hundreds of years. Choreito is a kampo preparation for preventing urinary calculi and promoting stone passage.4,5
A prospective randomized study was carried out to compare the efficacy of tamsulosin (0.2 mg/daily) and choreito in expelling ureteral stones after ESWL treatment.
Between July 2005 and April 2006, 102 Japanese male patients with ureteral stones greater than 4 mm who underwent ESWL at the Funabashi Clinic, Yokohama Rosai Hospital, and Chiba University Hospital were enrolled in this prospective study. All patients were evaluated using plain abdominal radiography, urinary ultrasonography, and/or drip infusion urography when a more accurate study of the urinary tract was necessary. Stone size was recorded for each patient. The local ethics committee granted its approval for the study. The treatment was fully explained to the patients before they provided written informed consent. The use of tamsulosin was not funded through health insurance. The exclusion criteria were: signs of urinary tract infection, severe hydronephrosis, multiple stones, diabetes, ulcer disease, non-functioning kidney, morbid obesity, and treatment with choreito, calcium antagonists, or alpha-1 adrenergic blockers.
All patients had a single ESWL session. All three hospitals used the lithotripsy module with electromagnetic shock wave head (Dornier lithotripter, Wessling, Germany; Stoltz SLX-MX, Tägerwilen, Switzerland; and Simens modularis variostar, Erlangen, Germany). Before ESWL treatment, the patients were randomly divided into three groups. Group A (38 patients) was given tamsulosin (0.2 mg per day). Group B (30 patients) was given choreito (7.5 g per day, by Tsumura & Co. Tokyo Japan). Group C (34 patients) was given no medication. Treatment commenced on the first day of ESWL and continued until stoneclearance was achieved. All of the groups were instructed to drink 2 L water per day and used diclofenac (50 mg suppository) on demand for pain.
Stone clearance was assessed 1, 7, 14, and 28 days after ESWL using plain abdominal radiography (KUB) and urinary ultrasonography. After 28 days, stone clearance was assessed every 2 weeks.
Successful clearance was defined as the absence of all stones on KUB or the presence of clinically insignificant asymptomatic residual fragments smaller than 3 mm in diameter. Patients who had infection, pain, or severe hydronephrosis, and in whom stone clearance could not be expected, underwent additional ESWL or ureteroscopy treatments; these patients were excluded from the study.
Student's t-test was used to compare continuous variables among the three treatment groups; the χ2 test was used to compare categorical variables. P < 0.05 was taken as indicating statistical significance.
The patients' characteristics are summarized in Table 1. There were no statistically significant differences among the three groups with respect to age and stone size.
Table 1. Patient characteristics
Mean age ± SD
56.76 ± 8.69
56.36 ± 9.61
52.29 ± 14.63
Mean stone size ± SD (mm)
10.61 ± 4.45
10.45 ± 5.17
9.85 ± 3.13
Proximal ureteral stones were noted in 27 of 38 (71.05%) group A patients, 23 of 30 (76.67%) group B patients, and 23 of 34 (67.65%) group C patients. Medial ureteral stones were noted in three of 38 (7.89%) group A patients, two of 30 (6.67%) group B patients, and three of 34 (8.82%) group C patients. Distal ureteral stones were noted in eight of 38 (21.05%) group A patients, five of 30 (16.67%) group B patients, and eight of 34 (23.53%) group C patients. In all groups, proximal stones were the most frequent, followed by distal stones, and then medial stones. There were no statistically significant differences among the groups with respect to stone location (Table 2).
Table 2. Stone location
The stone-free rate was 84.21% (32/38 patients) for group A, 90% (27/30) for group B, and 88.24% (30/34) for group C; the difference among the groups was not statistically significant (Table 3).
Table 3. Expulsion rate and expulsion time of the three groups
The mean expulsion time was 15.66 ± 6.14 days (range 1–30) in group A, 27.74 ± 25.36 days (4–90) in group B, and 35.47 ± 53.70 days (1–218) in group C. The mean expulsion times were significantly different between groups A and B (P = 0.0116) and between groups A and C (P = 0.0424), but not between groups B and C (P = 0.4982) (Table 3 and Fig. 1).
In group C, there was a tendency for stone size to be related to expulsion time (r = 0.351, P = 0.057). However, there was no relationship between stone size and expulsion time in group A (r = 0.289, P = 0.1098) or in group B (r = −0.212, P = 0.3021; Fig. 2).
Extracorporeal shock wave lithotripsy was introduced into routine clinical practice by Chaussy and colleagues in 19826 and is now the most widely used method for managing renal and ureteral calculi. The purpose of ESWL is stone fragmentation; it does not promote stone expulsion. In addition, ESWL can be quite expensive, and it often requires multiple treatments.7 Pace et al. suggested that, after the initial treatment, the stone-free rate after re-treating ureteral calculi with ESWL decreases significantly.8 Thus, fragmentation of these stones may be insufficient for complete stone clearance, which depends on many factors. Although stone size and location are the main factors affecting stone clearance, the internal anatomical structure of the ureter and stone composition appear to be unmodifiable factors. However, other possible causes of stone retention, such as infection, smooth muscle spasm, and edema formation, which can occur due to stone impaction or ESWL treatment, are modifiable factors.9,10
It is beneficial to improve these modifiable factors so as to promote stone expulsion. Various medications, such as nifedipine (a calcium antagonist), glyceryl trinitrate, prostaglandin synthesis inhibitors, antibiotics, and corticosteroid agents (deflazacort, methylprednisolone) have been investigated as spasmolytic agents that would promote the expulsion of ureteral stones, both in watchful waiting patients and post-ESWL patients.11–13 Recently, alpha-1 adrenergic blockers, which are used by urologists to treat lower urinary tract syndrome, have been noted to be useful.
In 1970, Malin et al.14 demonstrated the presence of alpha- and beta-adrenergic receptors in the human ureter, and alpha-adrenergic receptors in the animal ureter. The stimulation effect that alpha-adrenergic agonists have on ureteral contraction is dose-dependent. Noradrenaline, an alpha-adrenergic agonist, has a positive chronotropic effect that increases the frequency of ureteral peristalsis and a positive inotropic effect that increases muscle tone in high doses, which can lead to complete ureteral obstruction. For this reason, alpha-adrenergic stimulation decreases ureteral flow. The specific antagonists of the alpha-adrenergic receptors decrease the amplitude and the frequency of ureteral peristalsis; as a result, intraureteral pressure decreases and urine transport increases. Therefore, it was hypothesized that tamsulosin would increase the intraureteral pressure gradient around the stone and the bolus of urine located above the stone, as well as decrease peristalsis below the stone. As a result, with the decrease in pressure at the entrance to the urinary bladder, urine flow may eliminate the stone.
Based on the evidence, alpha-1 receptors have an important role in the physiology of ureteral expulsion. Several recent papers have proposed the use of alpha-1 blockers to facilitate ureteral stone expulsion.2,3,15,16 The addition of tamsulosin to medical therapy or ESWL for lower ureteral stones has been noted to have a positive effect. Resim et al. found that tamsulosin appeared to reduce the number of ureteral colic episodes and the severity of pain in patients who developed steinstrasse after ESWL.16 However, the tamsulosin dose (0.4 mg/daily) used in these papers is not the dose accepted in Japan. The accepted tamsulosin dose by Japanese health insurance is less than 0.2 mg. Though the safety of tamsulosin 0.2 mg has been established in Japan, the safety of 0.4 mg of tamsulosin has not been established in Japanese patients. Therefore, we used tamsulosin 0.2 mg in this study. Thus, in the present study, the efficacy of tamsulosin 0.2 mg/daily for expulsive therapy in patients with ureteral stone after an ESWL treatment was assessed. To the best of our knowledge, no previous studies have used a tamsulosin dose of 0.2 mg/daily, and this is the first such study in the Japanese population.
Despite the fact that most stones were located in the upper ureter in the present study, tamsulosin was effective in shortening the expulsion time; the expulsion time was significantly shorter in the tamsulosin group (group A) than in the other groups. The density of alpha-1 adrenoceptors has been shown to be higher in the distal ureter, though alpha-1 adrenoceptors are present in the proximal ureter and medial ureter.17 Davenport et al. reported that tamsulosin significantly reduced human proximal ureteral pressure.18 Our results support these previous findings that tamsulosin reduces proximal ureteral pressure and accelerates stone delivery. Alpha-1d subtype mRNA has been shown to be more highly expressed than alpha-1a subtype mRNA in each ureteral region.19,20 These reports suggest that an alpha-1d selective antagonist would be better than an alpha-1a antagonist. However, Tomiyama et al. reported that, in the hamster ureter, ureteral contraction was mainly mediated via alpha-1a adrenoreceptors, even though alpha-1d receptors were more prevalent than alpha-1a adrenoreceptors.21 If these findings were true for humans, then an alpha-1a adrenoreceptor antagonist treatment could become useful for promoting stone passage. Further comparative studies are needed to determine which type of alpha-1 adrenoreceptor antagonist is better for promoting stone passage.
In the present study, though the stone expulsion rate was lowest in the tamsulosin group, there were no statistically significant differences among the three groups in the stone expulsion rate (tamsulosin 84.21%, choreito 90%, control 88.24%); in fact, the stone expulsion rate was very good in each group, independent of the use of medication. Furthermore, the use of electromagnetic shock wave lithotripsy caused good stone fragmentation; this might have resulted in the finding that stone size was not related to the expulsion time in the groups given treatment. In fact, Dellabela et al. reported similar findings,22 and they believed that their findings were the result of corticosteroid treatment preventing edema and inflammation at the stone site. However, in the present study, corticosteroid treatment was not given. It is possible that, in the present study, tamsulosin decreased the obstruction-induced, phasic peristaltic contractions and maintained tonic contractions, which allowed early stone passage. Furthermore, choreito is usually used in Japan to treat acute cystitis. It prevents edema and inflammation and slightly increases urine volume,4 which would also facilitate the early passage of stones.
Several authors have indicated that tamsulosin reduces colic pain. However, this was not assessed in the present study. Further studies are needed to determine whether low dose tamsulosin can effectively prevent or reduce colic pain. In the present study, tamsulosin 0.2 mg/daily appeared to have a beneficial effect for expulsive therapy in patients with ureteral stone who had an ESWL treatment. Reduction of stone expulsion time should decrease the length of hospital stay, the duration of pain, the need for additional treatment, and the number of working days lost. However, in the present study, only a small number of cases were assessed. Thus, further studies are necessary.
In conclusion, tamsulosin 0.2 mg daily effectively decreased stone expulsion time following ESWL, not only for distal ureteral stones but also for proximal ureteral stones.